Human cells carrying mutations for a complex genetic disease can be repaired and reprogrammed so that they are indistinguishable from the cells of healthy individuals. Juan Carlos Izpisúa Belmonte, at the Center of Regenerative Medicine in Barcelona, Spain, and colleagues have generated 19 lines of so-called induced pluripotent stem (iPS) cells from patients carrying a variety of mutations that give rise to Fanconi anaemia, a rare and often fatal disease1. "We show that genetic correction, combined with iPS cell technology, can be used to produce disease-free cells with potential value for cell-therapy applications," explains Belmonte.

Though the cells have not yet been tested in patients or even animal models, it is an important proof of principle for both cell and gene therapy, says John Wagner, clinical director of the Stem Cell Institute at the University of Minnesota in Minneapolis. "The problem with gene therapy wasn't with the gene but the fact that [the gene] wasn't getting to the right cell. This is a new strategy that says now we can get many cells," he says. "It's very much boosted my enthusiasm for gene therapy, at least for this horrendous disease."

Both Belmonte and Wagner cite several factors that must be overcome before the procedure is ready to move into patients — first is developing better procedures for making the necessary cells. Cells from individuals with Fanconi anaemia typically do not proliferate well, and Belmonte found that the cells' genetic defects had to be repaired before they could be reprogrammed and could differentiate.

To get enough cells to make gene therapy feasible, Belmonte estimates that the reprogramming efficiency needs to be about 0.1%, which is the rate seen with the original 'Yamanaka technique' of using viruses to insert copies of four pluripotency genes into the cells. However, 'cleaner' techniques that transform cells without viral integration and with less risk of tumour formation are much less efficient. Furthermore, current techniques to differentiate haematopoietic progenitors from embryonic stem cells and iPS cells produce cells that seem unable to sustain long-term blood formation.

The biggest concern is making sure the transformed cells don't lead to malignant growth, says Belmonte. Tumours are a concern for any cell products derived from pluripotent cells, but because individuals with Fanconi anaemia are especially susceptible to leukaemias and skin cancers, their cells may have already accumulated mutations that make them prone to such problems.

Despite the risks, this strategy should be actively pursued therapeutically, says Wagner. Though bone marrow transplants can often treat Fanconi anaemia successfully, he says, the treatments can be painful, debilitating and emotionally draining for patients and their families. He adds that there are adult patients for whom bone marrow transplants are not an option, which provides a ready population of candidates for a clinical trial.

Establishing techniques to make the cells and to test them for efficacy and tumourigenicity in appropriate animal models will take five years at a very optimistic estimate, says Wagner, but he thinks the strategy is likely to work, eventually. "For moving this into a treatment, all the issues are likely to be addressable."

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